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Therapy Insight: type 2 diabetes mellitus and the risk of late-onset Alzheimer's disease

Abstract

A number of well-designed epidemiological studies have linked type 2 diabetes mellitus (T2DM) with an increased risk of Alzheimer's disease (AD). Several mechanisms could help to explain this proposed link, including insulin and insulin resistance, inflammatory cytokines, and oxidative stress. Obesity or physical inactivity might also influence AD through effects on hypertension, insulin sensitivity or inflammation. Typical AD pathology, such as amyloid-β deposits, might be exacerbated by insulin dysregulation, T2DM itself, or microvascular disease that is a consequence of T2DM. T2DM patients are not routinely evaluated for cognitive outcomes, and cognitive impairment in T2DM is rarely treated. Similarly, AD patients are not routinely evaluated for T2DM or hyperinsulinemia. Current treatments for AD have only modest benefits, and several drugs that target metabolic and inflammatory pathways are being evaluated, most notably the statins, which reduce LDL and inflammation but might not influence amyloid- deposition, an important precursor for AD. Although some evidence supports a potentially important role for peroxisome proliferative activated receptor agonists such as glitazones, at present there are no published randomized clinical trials in AD patients of any drugs that target insulin or insulin resistance. Clinical implications of the T2DM–AD link include cognitive evaluations of patients with T2DM, and potential benefits for such patients through treatment with statins or diabetes drugs that target insulin.

Key Points

  • Type 2 diabetes mellitus (T2DM) is no longer solely a disease of middle and old age; this condition is rapidly emerging as a serious health threat among younger adults and even adolescents

  • Numerous epidemiological studies have linked T2DM with an increased risk of Alzheimer's disease (AD)

  • Recent studies have explored the involvement of metabolic, inflammatory, vascular and oxidative pathways in AD etiology; these factors are also present in T2DM, and might provide an explanation for the link between T2DM and AD

  • No randomized trials of patients with T2DM have yet included patients with AD or dementia, although one study revealed that type 2 diabetics receiving therapy showed less deterioration on cognitive tests than untreated T2DM patients

  • Several lines of evidence support the idea that lifestyle interventions targeting obesity and exercise could reduce the development of cognitive impairment, and thereby reduce a proportion of AD cases

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Figure 1: Causal model for the potential links between type 2 diabetes mellitus and Alzheimer's disease.

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Acknowledgements

Acknowledgments to Nancy West, doctoral student at the University of Michigan, for her assistance with references and for her outstanding scientific thoughts.

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Correspondence to Mary N Haan.

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Haan, M. Therapy Insight: type 2 diabetes mellitus and the risk of late-onset Alzheimer's disease. Nat Rev Neurol 2, 159–166 (2006). https://doi.org/10.1038/ncpneuro0124

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